Cessation of chronic treatment with the centrally acting antihypertensive agent clonidine has resulted in a withdrawal syndrome. The symptoms of this withdrawal (tachycardia, agitation, hypertensive overshoot) suggest sympathetic hyperactivity. We have recently demonstrated a similar syndrome in the rat and have demonstrated that indeed sympathetic hyperactivity occurs during clonidine withdrawal. The occurence of stereotyped withdrawal means by definition that clonidine produces physical dependence. We also find that clonidine withdrawal in rats is associated with increased activity of the locus coeruleus, the primary noradrenergic cell group in the brain. The objectives of this work are: (1) to elucidate the mechanism of clonidine physical dependence (by testing a hypothesis derived from our data); (2) to determine if hypertensive animals (especially SHR) differ from normotensive animals in the hemodynamic characteristics of their withdrawal syndrome; and (3) to study structure activity relationships of centrally acting antihypertensive agents with respect to withdrawal producing liability to determine if the two activities (antihypertensive, withdrawal) are separable. In preparation for these major objectives we will characterize (hemodynamic and biochemical changes as a function of drug dosage, duration treatment, etc.) a well-defined animal model of the clonidine withdrawal syndrome. These studies will provide an increased understanding of the clonidine withdrawal. More importantly, the experiments testing our working hypothesis of mechanism (or some derivative of that hypothesis) may provide an explanation of the physical dependence to clonidine at a molecular level. If so, it would be the first in vivo physical dependence phenomena to be explained at this basic level. At a practical level, if we find that the antihypertensive activity and withdrawal liability are separable of the basis of chemical structure, these data may provide the rationale for the design of effective antihypertensives acting by the same mechanism as clonidine, but devoid of withdrawal liability.